alpha, alpha, disubstituted succinic acids and anhydrides



Patented Mar. 9, 1954 UNITED STATES PATENT OFFICE m DEUBSIHPUIE SUCCINIC ACIDS D ANHYDRIDES James M. Spragne, Drexel and Edward J. Cragoe, J12, Ridley Park, 2a., assignors to-Merek & 00., line, a corporation of New Jersey Noprawing. I Application November 4,1949, .Serial No. 125,648

R! I R:CC 0 on /0 Hz o in w ic R and R are ehe e om th above recited pairs of substituents.

he cms un s i s nvent c ha e u il ty as intermediates for the production of various chemic c ounds r orto h s i vent t e more c mplex aa-disubstitu ed sue inic adds were unknown and their availability, as a feature oi this in en n o ens a w de .i e d fo syntheses of new chemical compounds.

Further, certain of the compounds or this gnyention possess the characteristic of suppressing gastric, secretion, which characteristic finds utilityin the study and treatment of gastric ulcer.

The ,a..diarylsuccinic acids in which one or both of the a ryl nuclei are substituted by one or more chlorine atoms, are particularly useful in the suppression of gastric secretions. Additionally, other compounds of this invention possess antibacterial activity. Illustrative of thecompounds possessing antibacterial activity are the a-arylfalkylesuccinic acids and anhydrides in which the alkyl radical contains six or more carbon atoms.

P or o hi nve ti n only the simpler l dialkyl-succinic acids and anhydrides were known an of t d h tyn c mm ne en y a, adi plf1eny1 Sl1 CCiniC acid was known, A feature of this invention is making available heretofQre unknown a-aryl-a-alkyl-succinic acids and anhyd d s and wa n-Me l containing at least we h it enw ee n e c ds and, anhydrides- It is w possible to p epar these comp unds b virtue oi the ailability oi the nte meliate substituted-alkylidenecyanoacetates described in the co-pending application of Edward J. Cragoe filed herewith and entitled Alkylidenecyanoacetates and an Improved Process for Preparation Thereof."

lhe compounds of this invention can beprepared by starting with the proper disubstitutedalkylidenecyanoacetate ester and treating it with ydro en cyanide to produce the di ano .est whi h c h b d yzed successively by ur id a alkali a yield ni ro en. nee succinic acid. The corresponding suecinic anhydrides can be obtained by refluxing the suceinic acid with acetyl chloride or thionyl chloride and purifying the anhydride by distillation.

h reactions n elv d can be; represented y the following equation:

in which (A rep ents. the alkyl noae aste :3 he d CShIlQ e C e uec n id. a d. D th sueei a e h ricl R nd'R' a t e des red su s i uen on h su eini aci or acid an yd isie and ha h m an n s her ef ore set ou in general the preparation of the cyano esters s a c p i he by add n a sa ra d ueeu s lu i n of p as um an d to n e hel so ution of h a ky n an acet te, wa min h mix e er a i in tes and cidif ing wi hydroqhloric aeidhe i yane es e s a usua l oi hich. arec n enien ly pur fied and i general harac eri ed as th i d r ti es tha is the'su einie. acid r succin c a d enhydride i tinll s ef h d c ane ste is earne "by re u ng th ester with a x ur e msistins 9i c ncentrated sulfur acid, gla ial aceti ac d and s m a e Th ef u ng is ontin ed f r approx ately 12 to 15'hou s- A setisfacto y medium fe he hydr l s s s sulfuri ac d 0% acetic ac d 4 and wat r .9%- eiter reflux ng. the. mixture is poure into wate the. esulting Qil ex racted with benzene. The benzene is removed by distillation, convenpoured onto crushed ice (640 gm.).

iently at reduced pressure, and the residual oil refluxed with 20% potassium hydroxide until ammonia is no longer liberated. At the end of this time the reaction mixture is cooled and acidified and the succinic acids separate. The acid can be recovered by filtration if a solid, or by extraction with benzene followed by removal of the benzene by distillation, if a liquid. The advantage of the alkaline hydrolysis is that nitrogen free succinic acids are obtained by this procedure.

The succinic acid anhydrides can be obtained by refluxing the corresponding succinic acid with acetyl chloride or thionyl chloride and purifying the anhydride by distillation.

The compounds embraced by this invention are.

illustrated by:

Physical Constants Compound Press a-phenyl-a-ethylsuccinic acld 148-9 a-phenyl-a-n-amylsuccinic anhydride 162 l 1. 5159 a-phenyl-a-n-hcptylsuccinic anhydride 170-2 2 1. 5081 a-phenyl-a-n-undecylsuccinic anhydride 193-6 1-2 1.5010 a-phenyl-a-(2-cycloherylethyl) succinic anhydride 185-8 1-2 1. 5301 a-phenyl-a-(-cyclohexylpe tyl) succlnlc anhydrlde. 210 1-2 1. 5210 a-(4-n-butylphenyl)-a-n-hexylsucclnie anhydride 95-8 178-180 1-2 1 1. 5055 a-a-dlphcncthylsuccinic acid... 155-6 a phenyl a (4 chlorophenyl) suecinie acid 187-8 a-(4-chlorophenyD-a-(2-chlorophenyhsuccinic acid 195-6 a-n-di-(4-chlorophenyD-succin- 1c acid 188-9 pylidenecyanoacetate (61 gm, 0.196 mole) was dissolved in ethanol (80 ml.) and treated with a solution of potassium cyanide (25.5 gm., 0.39 mole) inwater (80 ml.).- The orange solution was heated, with stirring, on a steam bath for minutes, then cooled, diluted with water (100 ml.) and accidified with excess concentrated hydrochloric acid. The oily layer that separated was extracted with benzene (three '75 ml. portions) and the combined extracts washed with water.

The benzene was removed by distillation at reduced pressure. The residual oil (66 gm. 99%) is ethyl 2,3-dicyano-5-cyclohexyl-3-phenylpentanoate. This material was added to a solution composed of concentrated sulfuric acid (248 gm.)

' lacial acetic acid (262 am.) and water (50 ml.).

The mixture was refluxed for 15 hours and then The oily layer that separated was removed by benzene extraction (three 100 ml. portions). The benzene was removed by distillation from the combined extracts and the residual oil treated with potassium hydroxide (185 ml.). The resulting solution was refluxed for 72 hours. After cooling, the solution was treated with decolorizing carbon,

filtered and the filtrate acidified with excess hydrochloric acid. The oily a-phenyl-a-(z-cyclohexylethyDsuccinic acid that separated was removed by extraction with benzene (three 100 ml.

4 sulfate. After removal of the benzene by distillation at reduced pressure, a waxy solid remained, yield, 59.6 gm. (94%) M. P., 100-110 C.

The a-phenyl -a.-(2 cyclohexylethyl) succinic acid was refluxed for 2 hours with acetyl chloride (75 ml.) The excess acetyl chloride was removed by distillation and the residue fractionated at reduced pressure. The yield of material boiling at 184-8 C. at 1-2 mm. of Hg is 30.4 gm. (54%). Refractionationgives 29.3 gm. (52%) of material boiling at 185-'8 C. at l-2 mm., n =l.5301.

Example 2.a.Phe7L1/Za-(7Z heptyl) succinic anhydride is prepared from ethyl l-phenyloctylidenecyanoacetate in a manner similar to that described in Example 1. The yield was 56%; B. R, 170-2 C. at 2 mm. of Hg; n 1.5081.

Example 3.a-'Phenyl-a-(5-cycloherylpentyl) succinic anhydride was prepared from ethyl poured onto ice (1 kgmJ.

l-phenyl- 6 (cyclohexyl) hexylidenecyanoacetate in a manner similar to that described in Example 1. The yield was 45%; B. P. 210 C. at 1-2 mm. of Hg; 11 1.5210.

Example 4.a- (4-n-butylphenyl) -a.-(1l-h8$yl) succinic anhydride is prepared from ethyl 1-(4- n-butylphenyl)- heptylidenecyanoacetate in a manner similar to that described in Example 1. The yield is 54%, M. P. -8 C., B. P. 178-180 C. at 1-2 mm. of Hg, 11 1.5055 (on supercooled liquid).

Example 5 .--a-Phn1,IZ-a- (4-chlor phenyl) succimc acid.-Ethyl phenyl(4-chlorophenyl) methylenecyanoacetate (101.4 gm., 0.326 mole) was dissolved in warm ethanol (147 ml.) and treated with a solution of potassium cyanide (42.4 gm., 0.65 mole) in water (180 ml.). The clear yellow solution that resulted was heated on a steam bath. with stirring, for 15 minutes. The solution was cooled and acidified with excess concentrated hydrochloric acid. The product separated nearly quantitatively as a viscous oil. The mixture was diluted with water and extracted with benzene (three ml. portions). The benzene was removed by distillation at reduced pressure. The residual oil, ethyl 3-phenyl-3-(4-chlorophenyl)-2-3-dicyanopropionate, weighed 109 gm.

This ethyl 3-phenyl-3-(4-chlorophenyl)-2-3- :dicyanopropionate Was added to a mixture of glacial acetic acid (431 gm.) concentrated sulfuric acid (409 gm.) and water (83 ml.). The mixture was refluxed for 15 hours, cooled and The oil which separated soon solidified. This material was removed by filtration, washed with water and dissolved in '20 potassium hydroxide solution (305 ml.) The solution was refluxed for 72 hours, cooled, diluted with water (300 m1.), treated with decolorizing charcoal and filtered. The filtrate was acidified with excess hydrochloric acid; the oil that separated soon solidified.

The yield of crude a-phenyl-a-(4-chlorophenyl) succinic acid was 98.5 gm. (100%), M. P.

' 157 C. Successive recrystallizations from a mixture of acetic acid and water gave 75.7 gm. (77%) of product melting at 187-188 C.

Example 6.-a- (Z-chlorophenyl) -a-(4-chlorophenybsuccimc acid, is prepared from ethyl (2- chlorophenyl) (4 chlorophenyl) methylenecyanoacetate in a manner similar to that described in Example 1. The yield was 47%; M. P. -6 C.

Similarly a-phenyl a (2 chlorophenyDsuccinic acid can be prepared from ethyl phenyl (2-chlorophenyl) methylenecyanoacetate.

Further, by using procedures similar to Exsample 1, and similar molar portions of ethyl 1- 4 hydroxyphenyl propylidenecyanoacetate, ethyl phenyl (4 methoxyphenyDmethylenecyanoacetate, ethyl 9 fluorenylidenecyanoacetate, ethyl 2-camphanylidenecyanoacetate, and ethyl 3,3-dimethyl-2-buty1idenecyanoacetate, it is possible to obtain respectively a-ethyl-a-(4- hydroxyphenyDsuccinic acid, a-phenyl-a-(4- methoxyphenyDsuccinic acid, Q-carboxyfluorene-Q-acetic acid, 2-carboxycamphane-2-acetic acid, and a-methyl-a-t-butylsuccinic acid.

It is to be realized that in the hydrolysis of the intermediate dicyano compounds possessing an aryl nucleus containing a labilizing group (such as hydroxy or methoxy) milder acid conditions are desirable. For example, a suitable hydrolysis medium for 2,3-dicyano-3-phenyl-3- (4-hydroxyphenyl)propionate consists of concentrated sulfuric acid (35%), glacial acetic acid (35%) and water (40%). Milder hydrolysis media can be chosen from solutions obtained by diluting a solution of 6 parts by weight concentrated sulfuric acid and 4 parts of water with up to six parts of glacial acetic acid.

In the specification and claims, the term aryl is intended to embrace phenyl or substituted phenyl radicals and the term aralkyl to embrace phenalkyl or substituted phenalkyl radicals, the substituent group, in either case, being of the type hereinbefore mentioned.

What is claimed is:

1. a Phenyl a (mono-halophenyl) succinic acids.

2. a-Phenyl-a (mono-chlorophenyl) acids.

3. a-(2-chlorophenyl) a. (4 chlorophenyl) succinic acid.

4. a-(lower-alkyb-a-phenyl succinic acids.

5. a-Phenyl a (5 cyclohexylpentyl)succinic acid.

succinic 6. A compound chosen from the class consisting of RI n-c-ooon rmwooon and in which R. and R are selected from the groups consisting of (1) where R is lower alkyl and R is a phenyl radical, (2) where R and R respectively is a phenalkyl radical and (3) R and R respectively is a phenyl radical and at least one phenyl nucleus is mono-halo substituted.

JAMES M. SPRAGUE. EDWARD J. CRAGOE, JR.

References Cited in the file of this patent 1936-1946, p. 9150, 2nd col.; p. 9152, 2nd col.

Maerae et al.; Chem. Abstracts, vol. 29, p. 1078 (1935).

Siddiqui et al.; Chem. Abstracts, vol. 36, p. 5470 (1942).

Beilstein (Handbuch, 4th ed.) vol. 9, 2nd sun. page 633 (1949). 

6. A COMPOUND CHOSEN FROM THE CLASS CONSISTING OF 